Understanding mechanisms of lung destruction in patients with non-tuberculous mycobacterial pulmonary infection

MMP-1 and TIMP-1 levels were measured by ELISA, and gene expression was assessed via RT-qPCR. HIF-1α involvement was evaluated using DMOG (stabiliser) and PX-478 (inhibitor), with protein expression analysed by Western blot. Pharmacological inhibitors targeting PI3K/Akt, MAPKs, NF-κB, and CREB were used to dissect regulatory pathways.<br><br>M. avium infection significantly increased MMP-1 transcription and secretion, with hypoxia further amplifying this response.

Hypoxia also suppressed TIMP-1, shifting the MMP-1:TIMP-1 balance toward proteolysis. HIF-1α was stabilised by infection alone and further enhanced under hypoxia. HIF-1α stabilisation increased MMP-1 secretion, while inhibition reduced it dose-dependently.

PI3K/Akt and p38 MAPK were key mediators of hypoxia-induced MMP-1 expression, while NF-κB inhibition suppressed MMP-1 under both oxygen conditions. Network analysis revealed crosstalk among PI3K, p38, NF-κB, and CREB, forming a coordinated regulatory axis.<br><br>In conclusion, M. avium infection and hypoxia synergistically drive MMP-1 overexpression in macrophages via HIF-1α and interconnected signalling pathways, contributing to lung matrix degradation in MAC-PD and identifying potential therapeutic targets.<br><br><i>Thesis is embargoed until 31 July 2030.</i><br>